UWCCC Cancer Genetic and Epigenetic Mechanisms (GEM) Program Summary Co-Leaders: Emery Bresnick and Michael Newton PROJECT SUMMARY/ABSTRACT As genetic and epigenetic mechanisms underlie human cancer initiation and progression, components of these mechanisms represent extremely promising targets for cancer prevention, diagnosis, and therapy. Considering the multitude of regulatory factors involved, and the many unanswered mechanistic questions, our vision is that much of the mechanistic knowledge and druggable space remain to be discovered. Thus, from both fundamental and clinical/translational perspectives, elucidating cancer genetic and epigenetic mechanisms continues to hold great promise. The UWCCC Cancer Genetic and Epigenetic Mechanisms Program (GEM) consists of 27 highly collaborative members spanning 13 departments and 6 schools at UW-Madison. The program members include basic and translational scientists conducting multidisciplinary research, with 3 members directing clinical cancer research programs and engaged in patient care. Senior members actively mentor junior faculty, and additional faculty recruitments are ongoing. During the prior funding period, GEM members published 453 papers, many of which appeared in high-impact journals including Cancer Cell, Mol. Cell, Science, Science Trans. Med., Nature Chem. Biol., J. Clin. Invest., and Genome Res. The 27 GEM members brought in a total of $9.98 M in direct cost cancer-relevant funding for which they are the PI (NIH total, $5.79 M, of which NCI, $1.25 M). GEM Thematic Aims are: 1) Discover and elucidate cancer genetic mechanisms; and 2) Discover and elucidate cancer epigenetic mechanisms. Multidisciplinary GEM teams are analyzing genetic and epigenetic mechanisms in breast, prostate, sarcoma, myeloid leukemia, and other cancers. The discoveries are used to develop new paradigms in cancer biology, and via new intra- and inter- programmatic collaborations, are applied toward clinical trials to improve cancer prevention, diagnosis, and therapy. GEM-derived methodological/technological innovations continue to dramatically enable GEM and broader UWCCC cancer research. An overarching theme is our invention and deployment of powerful strategies to discover and elucidate cancer mechanisms and enable diagnostic and therapeutic modalities unlikely to emerge from existing paradigms.